rs121908849

chr3-189866712-G-Achr3-189866712-G-Cchr3-189866712-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003722.5(TP63):c.797G>A(p.Arg266Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.90

Genes affected

TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 6) in uniprot entity P63_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003722.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-189866712-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1486558.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TP63
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-189866712-G-A is Pathogenic according to our data. Variant chr3-189866712-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.797G>A	p.Arg266Gln	missense_variant	6/14	ENST00000264731.8
TP63	NM_001114980.2	c.515G>A	p.Arg172Gln	missense_variant	4/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.797G>A	p.Arg266Gln	missense_variant	6/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.515G>A	p.Arg172Gln	missense_variant	4/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2011	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	The R266Q pathogenic variant in the TP63 gene, also referred to as R227Q due to the use of alternative nomenclature, is a common pathogenic variant that has been reported several times in association with Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) syndrome (van Bokhoven et al., 2001; Maclean et al., 2007; Sripathomsawat et al., 2011; Su et al., 2013). In vitro functional studies demonstrated that the R266Q variant enhances the transactivation of some TP63 targets and up-regulated the expression of mRNA and protein for TP63 target genes (Khokhar et al., 2008). The R266Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R266Q variant is a semi-conservative amino acid substitution, and occurs at a position that is conserved across species. We interpret R266Q as a pathogenic variant. -

ADULT syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

TP63-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP63 function (PMID: 18626511). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 6550). This variant is also known as R227Q. This missense change has been observed in individual(s) with TP63-related conditions (PMID: 11462173). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 266 of the TP63 protein (p.Arg266Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;M;M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.79	P;D;P;D;P;P;P;P;.;P;.
Vest4		0.96
MutPred		0.97		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;.;.;.;
MVP		1.0
MPC		0.74
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908849; hg19: chr3-189584501; COSMIC: COSV53200099; COSMIC: COSV53200099;